Bacterial infections of the central nervous system (CNS) are an important cause of morbidity and mortality. The major spirochetal infections of humans causing CNS infection and neurological disease include syphilis, leptospirosis, Lyme disease and relapsing fever (RF). The factors responsible for CNS invasion and injury in spirochetal infections are poorly understood. Our laboratory has been studying the pathogenesis of spirochetal CNS infection with RF and Lyme disease, referred to as neuroborreliosis. Immunocompetent mice inoculated systemically with the RF spirochete Borrelia turicatae develop relapsing spirochetemia with mild meningitis and residual brain infection but without brain injury. In the absence of B cells that produce the antibodies needed to clear the infection, mice develop constant high level spirochetemia, persistent CNS infection, and widespread microglial activation without brain injury. These observations suggest that the brain is well protected from injury during RF borreliosis. The recent finding that large amounts of the cytokine Interleukin 10 (IL-10) are produced in humans and experimental animals with RF borreliosis suggests that IL- 10 plays an important protective role in this infection. The discovery that exogenous recombinant IL-10 reduces clinical disease and brain inflammation and lowers the pathogen load in B cell deficient mice infected with Borrelia turicatae also supports this. Furthermore, IL-10 deficiency in B cell deficient mice resulted in higher pathogen load and more severe microvascular injury in the brain and other organs and early death from intracerebral/subarachnoid hemorrhage. These results support a fundamental protective role for IL-10 in RF borreliosis. In IL-10 deficient mice brain microvascular injury was much more severe with serotype 2, which causes higher spirochetemia and more systemic production of IL-10 than isogenic serotype 1, which causes higher CNS infection and greater cerebral production of IL-10 than serotype 2. This suggests an important neuroprotective function of IL-10 at the level of the blood-brain barrier. The finding that one could utilize IL-10 to protect the blood brain barrier during infectious or inflammatory disorders is of potential clinical relevance. The goal of this R21 exploratory application is to study the protective role of IL-10 in RF borreliosis in immunocompetent mice. Our main assumption is that IL-10 produced in response to the infection both systemically and in the brain protects the brain in general, and the cerebral microcirculation in particular, from injury. The specific hypothesis for this project is that IL-10 is essential during spirochetal infection to protect the integrity and preserve the function of the blood brain barrier. We propose to study this hypothesis with the following 3 specific aims: 1- Study the production of IL-10 by immunocompetent mice during acute and residual brain infection with B. turicatae. 2- Investigate the consequences of IL-10 deficiency to the brain parenchyma and cerebral blood vessels during infection with B. turicatae. 3- Determine whether IL-10 protects the function of the blood-brain barrier during infection with B. turicatae. PUBLIC HEALTH RELEVANCE: Infection by a group of bacteria called spirochetes is an important cause of brain disease in humans. Our preliminary results indicate that Interleukin 10 may be very important to protect the brain blood vessels from damage during this infection. We propose to study this in a mouse model of spirochetal brain infection. [unreadable] [unreadable] [unreadable]